05/11/2016. Human urate homeostasis. Tophi and Frequent Gout Flares Are Associated With Impairment to Health Related Quality of Life

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1 Prevalence per 1000 inhabitants SF-6D Health Utilities 05/11/2016 Giovambattista Desideri UO Geriatria Università degli Studi dell Aquila Tophi and Frequent Gout Flares Are Associated With Impairment to Health Related Quality of Life 0,8 0,75 0,7 0,688 0,685 L iperuricemia cronica nell anziano con o senza deposito di urati: cause e trattamento 0,65 0,6 0,55 0,5 0,627 0,635 0,45 0,4 RA OA SLE Gout Khanna P et al. Health and Quality of Life Outcomes 2012, 10:117 Epidemiology of gout and hyperuricaemia (SUA >6 mg/dl) in Italy during the years Hyperuricemia Males Hyperuricemia Female Gout Males Gout Females Human urate homeostasis Oxidative stress Humans and higher primates Rest of mammals Uricase over 85 Trifirò G, et al. Ann Rheum Dis (2011). Hediger MA et al. Physiology (Bethesda) Apr;20:

2 Prevalence of gout in men in New Zealand (Maori) compared with men of European descent Associations of purine-rich food groups with gout, from the Health Professionals Follow-up Study (HPFS) Klemp P et al. Ann Rheum Dis 1997;56:22 6; Roddy E et al. Rheumatology 2007;46:1441 4; Lennane GA et al. Ann Rheum Dis 1960;19: Choi HK et al. N Engl J Med. 2004;350: Associations of alcoholic beverages with gout, from the Health Professionals Follow-up Study (HPFS) Summary of the effects of beer, liquor and wine on SUA or gout by study Choi HK et al. Lancet. 2004;363: MacFarlane LA et al. Rheum Dis Clin North Am November ; 40(4):

3 Sugar Sweetened Beverages and Serum Uric Acid levels in Adolescents Vitamin C Intake and Serum Uric Acid Concentration in Men Nguyen S et al. J Pediatr June ; 154(6): Gao X et al. J Rheumatol September ; 35(9): Age- and sex-adjusted serum uric acid levels according to categories of coffee, tea, and caffeine intake: NHANES-III Summary of the effects of diet on risk of gout Vegetable proteins SUA LEVELS Beer, liquor, wine* Meat Seefaood Fructose/sugar -sweetened beverages Dairy Coffe Vitamin C SUA LEVELS cherries Choi HK et al. Arthritis Rheum Jun 15;57(5): MacFarlane LA et al. Rheum Dis Clin North Am November ; 40(4):

4 Dose-Response Association and CVD risk factors with Hyperuricemia Effects on Uric Acid Metabolism of the Drugs Drugs that lower serum uric acid Drugs that raise serum uric acid Juraschek SP et al. PLoS One. 2013;8(2):e Moriwaki, J Bioequiv Availab 2014, 6:1 The therapeutical management of chronic hyperuricemia in the third millennium What we would like to treat/prevent by urate lowering treatment? Flares, tophi, nephrolithiasis and subclinical damage? Cardio-nephro-metabolic protection (?) How we can reduce serum uric acid? Lifestyle Drugs The therapeutical management of chronic hyperuricemia in the third millennium What we would like to treat/prevent by urate lowering treatment? Flares, tophi, nephrolithiasis and subclinical articular damage? Cardio-nephro-metabolic protection (?) How we can reduce serum uric acid? Lifestyle Drugs 4

5 Gout: The Fashionable Disease Likelyhood ratio for various features in the diagnosis of gout - EULAR "the disease of kings "rich man's disease Ann Rheum Dis 2006;65: Gout in the elderly: (a)tipical features Gout is one of the most painful type of arthritis However, gout in the elderly tend to be more indolent while gout flares tend to be more polyarticular Given the chronicity of gout, elderly patients tend to have an increased incidence of tophi, especially of the elbows and hands Gout in the Elderly can be mistaken for changes that are usually attributed to OA or RA The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules. Tophi can supervene on Heberdenʼs and Bouchardʼs nodes. 5

6 Asymptomatic articular damage in hyperuricemia Asymptomatic articular damage in hyperuricemia Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage, known as the double contour sign. Pineda et al. Arthritis Research & Therapy 2011, High Serum Uric Acid Hyperuricemia and gout: time for a new staging system? The therapeutical management of chronic hyperuricemia in the third millennium A proposed revised staging system for hyperuricaemia and gout, based on the American Heart Association heart failure staging system. What we would like to treat/prevent by urate lowering treatment? Flares, tophi, nephrolithiasis and subclinical articular damage Cardio-nephro-metabolic protection (?) How we can reduce serum uric acid? Lifestyle Drugs Dalbeth N et al. Ann Rheum Dis

7 Prevalence per 1000 inhabitants ASYMPTOMATIC HYPERURICEMIA 05/11/2016 Epidemiology of gout and hyperuricaemia (SUA >6 mg/dl) in Italy during the years Hyperuricemia and CV disease Hyperuricemia Males Hyperuricemia Female Gout Males Gout Females over 85 Trifirò G, et al. Ann Rheum Dis (2011). High Serum Uric Acid Determinants of Hyperuricemia Xanthine oxydase Hypertension Modified from Rees F et al. Nat. Rev. Rheumatol. doi: /nrrheum

8 Determinants of Hyperuricemia L iperuricemia induce lo sviluppo di arteriolosclerosi in modo indipendente dalla pressione arteriosa. Xanthine oxydase excretion production Modified from Rees F et al. Nat. Rev. Rheumatol. doi: /nrrheum Mazzali et al, AJP Renal Physiol, 2002 Inflammasome: the missing link between gout and cardio-nephro-metabolic disorders? Inflammasome: the missing link between gout and cardio-nephro-metabolic disorders? 8

9 Hyperuricemia and Cardiorenal Metabolic Syndrome Alexander the great, Darwin, Harvey, Newton, Sydenham,. This association cannot be mere co-incidence. Chaudhary K et al Cardiorenal Med 2013;3: Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in Normal Healthy Adults Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? 100 medical students in the age group of 17 to 20 years Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral caffeine stimulant and thought to be responsible for better development of brain and more intelligence 1. Uric acid can increase locomotor activity in rats 2 Uric acid increases with emotional or physical stress 3 1 Orowan E. Nature 1955;175: Barrea CM et al. Pharmacol Biochem Behav1989;33: Patil U et al. International Journal of Recent Trends in Science And Technology Rahe RH et al. Psychosom Med 1974;36: Johnson RJ et al. J Comp Physiol B (1):

10 Uric Acid and Dementia in Community-Dwelling Older Persons: The InChianti Study elderly subjects (age 74.38±7.58 years) Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age, 59.9±18.9 mg/dl Serum UA, 4.5±1.4 mg/dl 108 community-dwelling adults aged 20 to 96 years Adjusted for UA tertile OR p age, sex, BMI, education 1) 3.82±0.53 mg/dl 2) 5.05±0.27 mg/dl 3) 6.72±1.24 mg/dl 1 (reference) 2.34 ( ) 3.06 ( ) alchohol, energy intake, smoking, chol, plasma vit. E 1) 3.82±0.53 mg/dl 2) 5.05±0.27 mg/dl 3) 6.72±1.24 mg/dl 1 (reference) 2.73 ( ) 3.63 ( ) renal function, hypertension, CVD, CBVD 1) 3.82±0.53 mg/dl 2) 5.05±0.27 mg/dl 3) 6.72±1.24 mg/dl 1 (reference) 2.62 ( ) 3.32 ( ) WM PS IF VeM WM PS IF VeM + MMSE basal score 1) 3.82±0.53 mg/dl 2) 5.05±0.27 mg/dl 3) 6.72±1.24 mg/dl 1 (reference) ( ) ( ) Ruggiero C, et al. Dement Geriatr Cogn Disord 2009;27: Vannorsdall TD, et al. Stroke. 2008;39: Could uric acid directly promote neuronal dysfunction and/or damage? 10

11 Ambivalenza biologica dell acido urico The therapeutical management of chronic hyperuricemia in the third millennium What we would like to treat/prevent by urate lowering treatment? Flares, tophi, nephrolithiasis and subclinical articular damage Cardio-nephro-metabolic protection (?) How we can reduce serum uric acid? Lifestyle Drugs Therapeutic Approaches to Chronic Hyperuricemia and Gout Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol, beer especially) are core aspects of management. Strength of recommendation (95% CI): 83 (75, 91) Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers. In The Pickwick Papers, the character Sam Weller warns his father that drinking will lead to gout. Manara M et al. Reumatismo, 2013; 65 (1): 4-21 Desideri G et al. High Blood Press Cardiovasc Prev (2014) 21:

12 Percentage of Subjects With SUA <6.0 mg/dl Prevalence (%) Proportion of patients (%) 05/11/2016 The purine degradation pathway Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat: APEX study Subjects (n =1.072) with serum urate level >8.0 mg/dl and gout and normal or impaired RF (creat. >1.5 to <2.0 mg/dl) / /262 ᵃ ᵇ ᶜ 4/9 170/ /269 ᵃ ᵇ 5/11 Patients with Normal Renal Function Patients with Impaired Renal Function Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function. a = p < 0.05 versus allopurinol in patients with impaired renal function; b = p < versus allopurinol in all patients; c = p < versus febuxostat 120 mg in all patients. 60/ / Allopurinol Febuxostat Berry CE et al. J Physiol. 2004; 555(Pt 3): Febuxostat 80 mg (n=262) _ Febuxostat 120 mg (n=269) _ 0/10 Allopurinol 300 mg * (n=268) _ Becker MA et al. Arthritis Research & Therapy 2010; 12: R63. Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients >65 Years of Age Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs b,c d a p=0.029 vs allopurinol b p<0.001 vs febuxosta 40 mg c p<0.001 vs allopurinol d p=0.004 vs allopurinol b,c a Jackson RL et al. BMC Geriatrics 2012;12:11 Jackson RL et al. BMC Geriatrics 2012;12:11 12

13 Systolic Blood Pressure (mmhg) Systolic Blood Pressure (mmhg) Diastolic Blood Pressure (mmhg) Diastolic Blood Pressure (mmhg) Prevalence (%) 05/11/2016 Selected concomitant medication use among elderly subjects during the CONFIRMS trial Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent. Starting doses are to be low and increased if necessary. Strength of recommendation (95% CI): 82 (76, 89) Jackson RL et al. BMC Geriatrics 2012;12:11 Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension Mean 24 hour blood pressure IMPORTANT QUESTIONS What threshold should be adopted to define hyperuricemia? Is hyperuricemia an independent risk factor for cardiovascular disease? Can we improve cardiovascular and renal outcomes by lowering sua levels? Pretreatment End of placebo phase Pretreatment End of allopurinol phase Pretreatment End of placebo phase Pretreatment End of allopurinol phase When should urate-lowering therapy be started? Borghi C et al. J Hypertens 2015;33: Feig DI et al. JAMA. 2008;27;300(8):

14 Comparison of randomized studies using xanthine oxidase inhibition in heart failure Reaction scheme for the XO- mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the dead end inhibitor, oxypurinol Tamariz L. et al. Circulation April Allopurinol inhibits uric acid formation but produces ROS Tamta H et al. Biochemistry 2006;71 Suppl 1:S Reaction scheme for the XO- mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the dead end inhibitor, oxypurinol Allopurinol and Cardiovascular Outcomes in Adults With Hypertension A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were studied: 10-year period Malik UZ et al. Free Radic Biol Med. 2011Jul 1;51(1): Allopurinol inhibits uric acid formation but produces ROS Tamta H et al. Biochemistry 2006;71 Suppl 1:S MacIsaac ML et al. Hypertension

15 Mean annual hospitalizations costs ( ) Mean annual total costs ( ) 05/11/2016 Febuxostat: RCT with CV outcome Trial Drug 1 objective Reference BP control Coronary endothelial dysfunction BP control Exercise tolerance in chronic angina Febuxostat vs. Allopurinol Febuxostat vs. Placebo Febuxostat vs. Placebo Febuxostat vs.placebo Clinic and ABPM Coronary flow ABPM Exercise test (ETT) NCT NCT NCT NCT ClinicalTrial.gov Total health care resource costs according to SUA levels Outpa ent Services Hospitaliza on Pharmaceu cal <=6 >6 <=7 >7 <=8 >8 Degli Esposti L et al, NMCD 2016 Total hospitalization costs according to SUA levels 2014 EULAR recommendations on the management of gout Other Hyperuricemia, kidney disease and CVD Recommendation 11: (ULT) Median: 9; min: 8; max: 9 All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached. SUA below 6 mg/dl (360 µmol/l) should be maintained lifelong CV mortality 0 <=6 >6 <=7 >7 <=8 >8 Stack AG et al. QJM 2013; 106: Degli Esposti L et al, NMCD